In Vitro and In Vivo Studies on HPMA-Based Polymeric Micelles Loaded with Curcumin

• DOI: 10.1021/acs.molpharmaceut.0c01114
• Publication Date: 2021-01-19T20:11:15Z
• Authors: Mahsa Bagheri; Marcel H. Fens; Tony G. Kleijn; Robin B. Capomaccio; Dora Mehn; Przemek M. Krawczyk; Enzo M. Scutigliani; Andrei Gurinov; Marc Baldus; Nicky C. H. van K...; Robbert J. Kok; Michal Heger; Cornelus F. van N...; Wim E. Hennink
• Keywords: pharmacokinetics parameters; Drug Carriers/chemistry; AF 4 results; in vitro uptake and localization; Drug Compounding/methods; Polymers; Pharmaceutical Science; Biochemistry; Drug Liberation/drug effects; Polyethylene Glycols; Mice; Polymers/chemistry; Drug Discovery; Antineoplastic Agents/chemistry; PBS; Micelles; Cancer; Drug Carriers; Tumor; 04 agricultural and veterinary sciences; nanomedicine; 3. Good health; Polyethylene Glycols/chemistry; Medicine; Molecular Medicine; Methacrylates; curcumin-induced cell death; Methacrylates/chemistry; Hydrophobic and Hydrophilic Interactions; Biotechnology; curcumin loading; 24 h incubation; Curcumin; Chemical Sciences not elsewhere classified; Cy 7-labeled mPEG 5 kDa; Drug Compounding; Polyesters; Biophysics; Antineoplastic Agents; asymmetrical flow field-flow fracti.; Cell Line; 0404 agricultural biotechnology; SDG 3 - Good Health and Well-being; Cell Line, Tumor; micelle; pharmacodynamics; Human Umbilical Vein Endothelial Cells; Animals; Humans; curcumin-loaded mPEG 5 kDa; pHPMA; 17.1; Particle Size; Acrylamides/chemistry; Pharmacology; Polyesters/chemistry; Acrylamides; mPEG 5 kDa; AF 4 analysis; Drug Liberation; human neuroblastoma xenograft model; HPMA-Based Polymeric Micelles Loaded; Neuro 2A cells; Curcumin/chemistry

Curcumin-loaded polymeric micelles composed of poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)) were prepared to solubilize and improve the pharmacokinetics of curcumin. Curcumin-loaded micelles were prepared by a nanoprecipitation method using mPEG5kDa-b-p(HPMA-Bz) copolymers with varying molecular weight of the hydrophobic block (5.2, 10.0, and 17.1 kDa). At equal curcumin loading, micelles composed of mPEG5kDa-b-p(HPMA-Bz)17.1kDa showed better curcumin retention in both phosphate-buffered saline (PBS) and plasma at 37 °C than micelles based on block copolymers with smaller hydrophobic blocks. No change in micelle size was observed during 24 h incubation in plasma using asymmetrical flow field-flow fractionation (AF4), attesting to particle stability. However, 22-49% of the curcumin loading was released from the micelles during 24 h from formulations with the highest to the lowest molecular weight p(HPMA-Bz), respectively, in plasma. AF4 analysis further showed that the released curcumin was subsequently solubilized by albumin. In vitro analyses revealed that the curcumin-loaded mPEG5kDa-b-p(HPMA-Bz)17.1kDa micelles were internalized by different types of cancer cells, resulting in curcumin-induced cell death. Intravenously administered curcumin-loaded, Cy7-labeled mPEG5kDa-b-p(HPMA-Bz)17.1kDa micelles in mice at 50 mg curcumin/kg showed a long circulation half-life for the micelles (t1/2 = 42 h), in line with the AF4 results. In contrast, the circulation time of curcumin was considerably shorter than that of the micelles (t1/2α = 0.11, t1/2β = 2.5 h) but ∼5 times longer than has been reported for free curcumin (t1/2α = 0.02 h). The faster clearance of curcumin in vivo compared to in vitro studies can be attributed to the interaction of curcumin with blood cells. Despite the excellent solubilizing effect of these micelles, no cytostatic effect was achieved in neuroblastoma-bearing mice, possibly because of the low sensitivity of the Neuro2A cells to curcumin.